6-halo-16-methyl-3, 20-diketo derivatives of the pregnane series



United States Patent 3,318,921 6-HALO-16-METHYL-3,20-DIKETO DERIVATIVES0F THE PREGNANE SERIES John Edwards, Mexico City, Mexico, Carl Djerassi,Palo Alto, Caliii, Howard J. Ringold, Shrewsbury, Mass, and GeorgeRosenkranz, Mexico City, Mexico, assignors, by mesne assignments, toSyntex Corporation, a corporation of Panama No Drawing. Filed Dec. 28,1961, Ser. No. 162,915

Claims riority, application 1Mexico, Apr. 28, 195?,

16 Claims. (c1. zen-$97.3

In the above formula Z and Z indicate a double bond between C-1 and C-2and between C-6 and C-7 respectively or a saturated linkage between C-land G2 and between C-6 and C-7 respectively. The methyl group at 0-16 isin the 0a or ,8 steric configuration; X represents fluorine, chlorine orbromine and when Z is a saturated linkage, these halogens may be in thea or 3 positions; and R represents hydrogen, hydroxyl or an acyloxygroup. The latter is derived from a hydrocarbon carboxylic acid of lessthan 12 carbon atoms, including saturated or unsaturated, straight orbranched chain aliphatic, cyclic or cyclic-aliphatic, optionallysubstituted with functional groups such as hydroxyl, acyloxy containingup to 12 carbon atoms, alkoxy containing up to 8 carbon atoms, amino orhalogen such as fluorine, chlorine or bromine. Typical esters are theformate, acetate, propionate, butyrate, enanthate, caproate, benzoate,hemisuccinate, aminoacetate, trimethylacetate, phenoxyacetate,phenylpropionate and fi-chloropropionate. The acyl groups may also bederived from sulfonic acids, sulfuric acid, phosphoric acid orhalogenated acids. The present invention also includes water-solublesalts of the esters such as the alkali salts of the hemisuccinates, thedisodium salts of esters with phosphoric acid or the hydrohalide saltsof esters formed with aminoacids.

The novel compounds of the present invention are progesterone likehormones which exhibit particularly anti-estrogenic and anti-androgenicactivity and also exhibit an antagonistic effect towarddesoxycorticosterone. The novel 3-keto u-hydroxy-6 3-(fluoro, chloro orbromo) derivatives, as for example 16a-methyl-6fl-fluoro-5u- 3,318,921Patented May 9, 1967 hydroxy 3,20-diones are useful agents exhibitingcentral nervous system repressing activity. The novel compounds are alsovaluable intermediates for the preparation of important6a-halo-l6-methylcortical hormones. Thus, by biological methods ahydroxyl group may be introduced at C11; for example, by incubation ofmethyl-6u-fluoro-pro-gesterone with Rhizopus nigricans ATCC 6227b, thereis obtained 16u-methyl-6a-fluorolla-hydroxyprogesterone, whereasincubation with bovine adrenal glands or with Cunninghamella bainieriATCC 9244 affords 16u-methyl-6u-fiuoro-llfl-hydroxyprogesterone. Bydehydration of the foregoing as by treatment with mesyl chloride indirnethylformamide-pyridine, thel6a-methyl-6a-fiuoro-1l-hydroxyprogesterones are converted into16a-methyl-6a-fluoro-A -pregnadiene-3,2O- dione, which compound upontreatment by the method of Fried et al., J. Am. Chem. Soc. 79, 1130(1957) gives the corresponding l6a-methyl-6o:--fiuoro-9a-halo-llfl-hydroxyprogesterone, which is a potent glycogenic agent.Alternatively, by condensation of the16a-methy1-6afiuoro-llot-hydroxyprogesterone or of16a-methyl-6ufluoro-ll-ketoprogesterone (formed by oxidation of thell-hydroxy compounds) with ethyl oxalate to form the C-21 oxalylderivative, followed by dibromination, rearrangement by reaction withsodium methoxide, formation of a 3-cycloethyleneketal, reduction withlithium aluminum hydride, acetylation at C-21, hydrolysis of the ketalgroup and oxidation of the A -dO11ble bond with phenyliodosoacetate astaught in copending application Serial No. 13,427 filed March 8, 1960there is obtained the 21-acetate of16a-methyl-6a-fiuoro-epihydrocortisone or of 16a methyl 16a fluorohydrocortisone, respectively. These compounds may be easily dehydratedas set forth above to form the 21- acetate of 16wmethyI-Ga-flUOrO-A-pregnadien-17a, 21-diol-3,20-dione which can then be transformed viathe method of Fried et al., supra, to l6a-methyl-6a-fluoro-9ot-halo-cortical hormones; the compounds can also be oxidized to formthe 21-acetate of 16a-methyl-6a-fluorocortisone.

The novel compounds of the present invention are prepared by a processillustrated in part by the following equation:

I (III) X r o=o I: J OHa I (IV 5 z 5 In the above formulae, X, Z and Zhave the same :aning as heretofore set forth; R and R are hydrogen acylof the type previously described. In practicing the process outlinedabove, l6a-methyl- ,6ot-oxidopregnan-3fl-ol-ZO-one acetate or165-methyl- ,6m-oxidopregnan-El/3-ol-20-one is treated with boronfluoride, hydrogen chloride or hydrogen bromide, to re the corresponding16-methyl-5a-hydroxy-6fi-(fluoro, loro or bromo) derivative. In the caseof the 16methyl-3fl-acetoxy-5a-hydroxy-6fl-halo derivatives, the :e3fi-aleohols are obtained by hydrolysis in a basic ediurn such aspotassium carbonate solution. The obtainedl6u-methyl-3fi,5a-dihydroxy-6,B-halo de- Iatives are oxidized byreacting an acetone solution of 1y of these compounds with dilutechromic acid, prefably 8 N chromic acid in dilute sulfuric acid, to forme corresponding 3-keto-compounds, namely, the16stethyl-6fl-halo-pregnan-Set-0L3,ZO-diones or the16pethyl-6,6-halo-pregnan-5u-ol-3,20-diones. Upon treatent with amineral acid, dehydration with or without rnultaneous inversion of thesteric configuration at C-6 effected. Thus, treatment with dilutehydrochloric acid acetic acid resulted in dehydration to afford thecorsponding l6a-methyl-6/3-halo-A -pregnen-3,20-dione or SB methyl 6 3halo A pregnene 3,20 dione re- |ectively. Treatment with dry hydrogenchloride in acial acetic acid solution resulted in the formation of ecorresponding 16a-methyl-6a-l1alo-A -pregnene-3,20- .one and 165 methyl6a halo A pregnene 3,20- vone, respectively. The 6,8-halo compounds canalso be inverted into the 6u-halo compounds by the treatment ith dryhydrogen chloride in glacial acetic acid.

Upon subsequent refluxing with selenium dioxide in ixture with tertiarybutanol and in the presence of catatic amounts of pyridine, there isobtained the l-dey'dro redivatives of the foregoing compounds; by re-Jxing with chloranil in ethyl acetate and acetic acid soluon, or inxylene, a .double bond is introduced at C6, 7. y combining these methodsof dehydrogenation there is stained the respective 1,4,6-trienes, whichmay also be .epared from the A compounds by refluxing with chloriil inn-amyl alcohol.

For introduction of the C-21 acetoxy group, the 16-,ethyl-6-halo-progesterones are transformed into their 1-iododerivatives by reaction with iodine and calcium ride in admixture withtetrahydrofuran and methanol. he resulting16-methyl-6-halo-2l-iodo-progesterones are ten refluxed with potassiumacetate in acetone under ihydrous conditions to produce thecorresponding 21- :etoxy compounds, namely the 21-acetates of the 165-iethyl-6fi-halo-desoxycorticosterones; 16 8 methyl 6w alodesoxycorticosterones; 16oz methyl 6,8 haloesoxycorticosterones andl6a-methyl-6u-halo-desoxy- Jrticosterone. By applying the methods ofdehydrogenaon set forth above, double bonds at C-1, 2 :and/or 7-6, 7 ofthe ZI-a-cetates of l6-methyl-6-halo-desoxy- )rticosterones areintroduced. The acetoxy group is ydrolyzed by conventional methods aswith dilute methnolic potassium hydroxide to the hydroxyl group which inthen be re-esterified with other acyl groups of the ype hereinabovedescribed.

The various steps set forth above which are described in detail in theexamples can be modified within wide limits. For example, dehydration atC-5 can be carried out with mineral acids such as sulfuric acid,hydrobromic or hydrofluoric acid and the acetic acid may be replaced byan inert solvent such as acetone; when the dehydration is carried outunder anhydrous conditions for a prolonged period of time, inversion ofthe steric configuration at C-6 accompanies the dehydration; when thedehydration is effected in the presence of water and/ or for a shortperiod of time, the fluorine atom at C-6 retains the ,B-configuration.The introduction of the additional double bond at C-l, 2 can also beeffected by conventional known microbiological methods, for example, byincubation with Corynebacterium simplex ATCC 6946.

The following specific examples serve to illustrate but are not intendedto limit the scope of the present invention.

EXAMPLE 1 To a solution of 5 g. of c-mthyl-50t,60-OXldOpregnan-35-ol-20-one acetate. (Ringold et al. US. patent applicationSer. No. 789,242 filed Jan. 27, 1959) in 250 cc. of ether and 250 cc. ofbenzene were added 5 cc. of freshly distilled boron trifluorideetherate. The reaction mixture Was left at room temperature overnight.After addition of water, the organic layer was separated, washed withwater, dried over anhydrous sodium sulfate and evaporated under reducedpressure. The residue was recrystallized from methylene chloride-hexaneaffording 16a methyl 6,8 fluoro pregnane 35,504 diol 20- one 3-acetate.

Following the same procedure there was treated 16B- methyl-5a,6u-oxidopregnan-3fi-ol-20-one (Djerassi US. patent application Serial No.792,964 filed February 13, 1959) thus yielding lSfl-methyl-Gfl-fluoropregnane-3,8,5- diol-20-one.

EXAMPLE 2 To a solution of 4 g. of16a-methyl-5a,6ot-oxido-pregnan-3,8-ol-20-one acetate in 40 cc. ofanhydrous chloroform, was added, over a period of 35 minutes, 30 cc. ofa 0.45 N solution of dry hydrogen chloride in chloroform, undercontinuous stirring and. maintaining the temperature around 0 C. Themixture Was then stirred at 0 C. for 1 hour further, diluted with Waterand the chloroform layer was separated, washed with aqueous sodiumbicarbonate solution and then with water, dried over anhydrous sodiumsulfate and evaporated under reduced pressure. Crystallization of theresidue from acetone-hexane gavel6a-methyl-6,B-chloro-pregnane-35,5a-diol-20- one-3-acetate.

Following the preceding technique, there was treatedl6fl-methyl-5a,6a-oxido-pregnan-3/8 ol-20-one, thus affording16fi-methyl-6,6-chloropregnane-3fl,5a-diol-20-one.

EXAMPLE 3 The starting compounds of the foregoing example were treatedfollowing the'procedure described in the same example except thathydrogen chloride was substituted by hydrogen bromide, thus furnishing16a-methyl6;3-brom0- pregnane-3,6,5a-diol-20-one, 3-acetate and16fl-methyl-6fibromo-pregnane-3/i,5a-diol-20-one.

EXAMPLE 4 A suspension of 5 g. of l6a-methyl-6fl-fluor0-pregnane-35,5u-diol-20-one-3acetate in 300 cc. of methanol was treated with asolution of 5 g. of potassium carbonate in 30 cc. of water; the mixturewas boiled under reflux for 1 hour and then cooled in ice and dilutedwith water. The formed precipitate was collected and recrystallized fromacetone hexane to yield l6a-methyl-6fi-fluoro-pregnane-3fi,5rx-diol-20-one.

When applying the above procedure to l6a-methyl-6/3- chloro pregnane35,50; diol 20 one 3 acetate 5 and 16a-methyl 6,8 bromo-pregnane 3,8,5diol-ZO- one-3-acetate there were correspondingly obtained: 16ozmethyl6,6 chloro pregnane 3,8,5 diol 20 one and16a-methyl-6B-bromo-pregnane-3fl,5a-diol-20-one.

EXAMPLE 5 A solution of 5 g. of l6amethyl-6/3-fluoropregnane-3B,5a-diol-20-one in 300 cc. of pure acetone was cooled to C., flushed withnitrogen and treated with 8 N chromic acid which was added in a slowstream until the color of chromic acid persisted in the mixture; the 8 Nsolution of chromic acid had been prepared by dissolving 26.7 g. ofchromium trioxide in 23 cc. of concentrated sulfuric acid and dilutingwith water to 100 cc. The mixture was stirred for minutes further at 0C., then diluted with water and the precipitate was collected, washedwith water, dried and recrystallized from acetone-hexane, thus giving160:- methyl-6B-fiuoro-pregnan-5a-ol-3,20-dione.

A slow stream of dry hydrogen chloride was introduced for 2 hours into asolution of 5 g. of the above compound in 200 cc. of glacial aceticacid, maintaining the temperature below 18 C. After pouring into icewater the precipitate was collected, washed with water, dried andrecrystallized from acetone-hexane. There was thus ob.- tained16a-methyl-6a-fiu0ro-progresterone, M.P. 8-1 60 C. [e] +57.

EXAMPLE 6 In accordance with the method of the preceding example therewere prepared 5 g. of l6a-rnethyl-6/3-fluoro-pregnan-5a-ol-3,20-dione,which was dissolved in 200 cc. of glacial acetic acid, treated with 2cc. of concentrated hydrochloric acid and allowed to react at roomtemperature for 2 hours. After diluting with ice water, the product wasisolated as described in the preceding example, thus yielding16a-methyl*6fi-fluoro-progesterone.

A part of the latter was treated with dry hydrogen chloride in glacialacetic acid, exactly as described in the preceding example, to produce16d-methyl-6a-fiuoroprogresterone, identical with the final compound ofsuch example.

EXAMPLE 7 By the methods described in Examples 5 and 6 there wasoxidized the 3 3-hydroxyl group of 16/3-methyl-6B-fluoro-pregnane-3fi,5a-diol-20-one to form the keto group at 0-3; theproduct was then dehydrated at C5 with or Without inverting the stericconfiguration at 0-6, to produce 16,3-methyl-6a-fluoro-progesterone orits 6fl-isomer, respectively.

Following the same procedures there were oxidized: 16a-methyl-6fi-chloropregnane-3,B-5a-diol one, 160:- methyl 6 8bromo-pregnane-3B-5d-diol-20-one, 16B methyl-69-chloropregnane-3B-5a-diol-20-one and 16/3-methyl-6fl-bromo-pregnane3,8-5a-diol-20-one, thus affording the corresponding 3-keto derivativeswhich upon dehydration at C-5 with or without invertion at C-6 producedcorrespondingly 16a-methyl-6u-chloro-progesterone,16amethyl-6abromo-progesterone, 16fi-methyl 6a chloroprogesterone and16fl-methyl-6a-bromo-progesterone or the respective 6fi-isomers thereof.

EXAMPLE 8 A solution of 5 g. of 16a-methyl-6a-fiuoroprogesterone in 37.5cc. of tetrahydrofuran and 23 cc. of methanol was treated undercontinuous stirring and in small portions with 7.5 g. of pure calciumoxide and then with 7.5 g. of iodine. The mixture was stirred until thecolor disappeared almost completely and then it was poured into icewater containing 22.5 cc. of acetic acid and 2.5 g. of sodiumthiosulfate. After stirring for 15 minutes the liquid was decanted andthe precipitate was collected by filtration thus giving16u-methyl-6u-fiuoro-2l-iodo-A -pregnene-3,20-dione.

The above compound was Washed with water, dried under vacuum and mixedwith 125 cc. of anhydrous acetone and 10 g. of recently fused potassiumacetate; the

mixture was refluxed for 18 hours under anhydrous conditions, theacetone was removed by distillation and the residue was treated withwater. The water was decanted from the oil which separated and thelatter was dissolved in methylene chloride; the solution was washed withwater, dried over anhydrous sodium sulfate and the methylene chloridewas distilled. The residue was refluxed for 15 minutes with a solutionof 1.3 g. of sodium bisulfite in 60 cc. of methanol and 12.5 cc. ofwater, the solvent was removed under reduced pressure and the residuewas treated with ice water; the precipitate was collected, Washed withwater, dried and recrystallized from acetone-water (8:1). There was thusobtained the acetate of 16a-methyl-6a-fluoro-desoxycorticosterone.

By the method described in the preceding example, the respective16-methyl-6-halo-progesterones were converted into the ZI-acetates of16ot-methyl-6,6-fluoro-desoxycorticosterone,1GB-methyl-6a-fluoro-desoxycorticosterone, 16,8-methyl-63-fluoro-desoxycorticosterone,

1 6a-methyl-6a-chloro-desoxycorticosterone,16u-methlyl-6B-chloro-desoxycorticosterone, 16fi-methyl- 6a-chloro-dcsoxycorticosterone,16,8-rnethyl-6B-chloro-desoxycorticosterone,l6u-rnethyl-6a-bromo-desoxycorticosterone,16a-rnethyl-6,8-bromo-desoxycorticosterone, 163-methyl-6ot-bromo-desoxycorticosterone and16B-rnethyl-6fl-bromo-desoxycorticosterone.

EXAMPLE 10 A mixture of 2 g. of 16a-methyl-6a-fluoroprogesterone, cc. oft-butanol, 800 mg. of selenium dioxide and a few drops of pyridine wasrefluxed for 48 hours under an atmosphere of nitrogen, filtered throughcelite and the solvent was evaporated under reduced pressure. Theresidue was dissolved in acetone, treated with decolorizing charcoalunder reflux for 1 hour, the charcoal was removed by filtration and theacetone was evaporated. The crude product was purified by chromatographyon neutral alumina, thus affording16a-methyl-6a-fluoro-1-dehydroprogesterone.

A mixture of 1 g. of the above compound, 2 g. of chloranil, 25 cc. ofethyl acetate and 5 cc. of acetic acid was refluxed under an atmosphereof nitrogen for 60 hours and then cooled. The mixture was washed with10% aqueous sodium hydroxide solution until the washings were colorless,then with water to neutral, dried over anhydrous sodium sulfate andevaporated to dryness under reduced pressure. Upon subsequentchromatography on neutral alumina there was obtained16a-methyl-6-fluoro- A -pregnatriene-3,20-dione.

EXAMPLE l1 2 g. of l6a-methyI-6a-fluoro-progesterone was subjected tothe reaction with chloranil described in the preceding example toproduce l6a-methyl-6-fluoro-A pregnadiene-3,20-dione; also following theprocedure described in the preceding example, there was then introducedthe third double bond at C1,2 by refluxing with selenium dioxide toobtain 16a-methyl-G-fluoro-A -pregnatriene- 3,20-dione, identical withthe final compound of the preceding example.

EXAMPLE 12 A mixture of 1 g. of 1Got-methyl-6/3fluoro-progesterone, 2 g.of chloranil and 30 cc. of n-amyl alcohol was refluxed for 72 hoursunder an atmosphere of nitrogen, diluted with water and extractedseveral times with methylene chloride; the extract was washed with 10%aqueous sodium hydroxide solution until the washings were colorless thenwith water, dried over anhydrous sodium sulfate and the solvent wasevaporated. By chromatography of the residue on neutral alumina therewas obtained 16ozmethyl 6-fiuoro-A -pregnatriene 3,20-dione, identicalwith the final compounds of Examples 10 and 11.

7 EXAMPLE 13 loro desoxycorticosterone-acetate, 160L-Il'lthy1 6B- lorodesoxycorticosterone acetate, l6fi-methyl 60cloro desoxycorticosteroneacetate, 16B-methyl 6dloro desoxycorticoste-rone acetate, 16ot-methyl6aomo desoxycorticosterone acetate, 16a-methyl 6,8- omodesoxycorticosterone acetate, l6/3-methyl 60como desoxycorticosteroneacetate, l6fi-methyl 65- omo desoxycorticosterone acetate and the6-dehydro .d 1,6-bisdehydro-derivatives thereof.

EXAMPLE 14 A mixture of 1 g. of the 21-acetate ofl6u-methyl-6uioro-desoxycorticosterone and 50 cc. of 0.5% metha- )l'iCsodium hydroxide solution was stirred for 1 hour 5 C., acidified withacetic acid, concentrated to a mall volume, diluted with ice water andthe precipitate as collected, washed with water, dried andrecrystallized om acetone-hexane, thus giving the freel6ct-methyl-6aloro-desoxycorticosterone.

-A solution of 500 mg. of the above compound in 5 cc. 5 pyridine wastreated with 1 cc. of propionic anhydride 1d the mixture was allowed toreact overnight at room mperature and then diluted with water, heated onthe cam bath for half an hour and cooled. The precipitate as collected,washed with water, dried and recrystallized 'om acetone-hexane, thusfurnishing the 21-pr0pionate E l6a-methyl6a-fluoro-desoxycorticosterone.

=Upon subsequent treatment with selenium dioxide by 1e method describedin Example 10 there was obtained 1e 2l-propionate of16OL-H16thY1-6OL-fill0l0 l-dehydroesoxycorticosterone; by reaction ofthe latter with chlornil, in accordance with the method described in theame example, there was then obtained the propionate f 16oc-1'I16fl1Yl6-fiuoro 1,6-bis-dehyd-ro-desoxycorticos- :rone.

EXAMPLE By applying the method described in the preceding exmple, the2l-acetate of 16a-methyl 6,8-fluoro-desoxyorticosterone was hydrolyzedto the free l6a-methyl 65- luoro-desoxycorticosterone.

500 mg. of the above compound was treated with 2.6 g. Ifcyclopentylpropionic anhydride and 5 cc. of pyridine, zept for 24 hoursat room temperature, diluted with water ll'ld extracted with methylenechloride; the extract was vashed with dilute hydrochloric acid andwater, dried )ver anhydrous sodium sulfate and the solvent wasevapiriated. 'By chromatography of the residue on neutral tlumina, therewas obtained the cyclopentylpropionate ofi6ot-methyl-6/i-fiuoro-desoxycorticosterone. By following he method ofdehydrogenation described in Example 10, here were then introducedadditional double bonds at 3-1, 2 and C-6, 7.

EXAMPLE 16 Following the technique described in Example 14 wereayd-rolyzed the 21-acetates of lGa-methyl 6OL-Ch10l'0-desoxycorticosterone, 16a-methyl 6B-chloro-desoxycorticosterone,16fl-methyl 6a-chloro-desoxycorticosterone, l6fl-methyl6p-chloro-desoxycorticosterone, l6oc-methyl-6ot-bromo-desoxycorticosterone, 16a-methyl 68-bromodesoxycortico-sterone, l6f3-met-hyl 6u-bromo-desoxycorticosteroneand 16fl-methyl 6,B-bromo-desoxycorticosterone thus affording thecor-responding ZI-free alcohols, which upon treatment with propionicanhydride by the method described in the same example, there wereobtained the respective 2l-propionates. Upon subsequent treatment withselenium dioxide by the method described in Example 10, there wereobtained the 21-propionate-ldehydro derivatives which by reaction withchloranil in accordance with the method described in the same exampleafforded the corresponding2l-propionate-1,6-bisdehydro-desoxycorticosterones.

We claim:

1. A compound of the following formula:

wherein X is selected from the group consisting of fluorine, chlorineand bromine.

11. A compound of the following formula:

wherein X is selected from the group consisting 9 12. A compound of thefollowing formula:

-w CH3 wherein X is selected from the group consisting of fluorine,chlorine and bromine.

13. A compound of the following formula:

wherein X is selected from the group consisting of fluorine, chlorineand bromine and R is selected from the group consisting of hydrogen anda hydrocarbon carboxylic acyl group of less than 12 carbon atoms.

14. A compound of the following formula:

CHzOR mm. egg

wherein X is selected from the group consisting of fluorine, chlorineand bromine and R is selected from the group consisting of hydrogen .anda hydrocarbon car boxylic acyl group of less than 12 carbon atoms.

15. A compound of the following formula:

oHzoR V wherein X is selected from the group consisting of fluorine,chlorine and bromine and R is selected from the group consisting ofhydrogen and a hydrocarbon carboxyl'ic acyl group of less than 12 carbonatoms.

16. A compound of the following formula:

CH8 6:0 w I 0:

ELBERT L. ROBERTS, Primary Examiner. LEWIS GOTTS, IRVING MARCUS,Examiners. H N A. FRENCH Assistant Examiner,

1. A COMPOUND OF THE FOLLOWING FORMULA: